Two types of intracerebral neuropeptides, orexin-A (OX-A, a peptide consisting of 33 amino acids) and orexin-B (OX-B, a peptide consisting of 28 amino acids), expressed in neurons localized in the hypothalamus of the brain, were found as endogenous ligands (Patent Literature 5 and Non Patent Literature 1) of G protein-coupled receptors mainly existing in the brain, that is, orexin receptors (Patent Literature 1, Patent Literature 2, Patent Literature 3, and Patent Literature 4). It is known that the orexin receptors include two subtypes, an OX1 receptor (OX1) as a type 1 subtype and an OX2 receptor (OX2) as a type 2 subtype. OX1 more selectively binds to OX-A than to OX-B, and OX2 binds to OX-A similarly to OX-B. It was found that orexins stimulate food consumption in rats and physiological roles as mediators of such peptides in a central feedback mechanism to regulate feeding behaviors have been suggested (Non Patent Literature 1). On the other hand, it was observed that orexins also regulate states of sleep and wakefulness, and therefore orexins are considered to lead to a novel treatment method for narcolepsy as well as insomnia and other sleep disorders (Non Patent Literature 2). Further, it has been suggested that orexin signals in the ventral tegmental area associated with narcotic addiction and nicotine addiction play important roles in vivo in neuroplasticity (Non Patent Literature 3 and Non Patent Literature 4). In addition, it has been reported that, when OX2 is selectively inhibited in an experiment using rats, ethanol addiction is alleviated (Non Patent Literature 5). Moreover, it has been reported that the corticotrophin releasing factor (CRF) associated with depression and anxiety disorder in rats induces orexin-induced activity, and there is a possibility of orexins playing important roles in a stress response (Non Patent Literature 6).
5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-di azepan-1-yl}-1,3-benzoxazole (MK-4305; suvorexant, Patent Literature 6) having a dual orexin antagonistic action for OX1 and OX2 has recently been released as an insomnia therapeutic agent. Further, E2006 (Lemborexant) has been clinically developed.
In Patent Literature 7, a compound represented by the following formula or a pharmaceutically acceptable salt thereof is considerably described as a compound that has an orexin receptor antagonistic action and is expected to have an effect in insomnia treatment.
[In the formula, Q is —CH— or a nitrogen atom, R1a and R1b each independently represent, for example, a C1-6 alkyl group, R1c represents a hydrogen atom, R2a, R2b, R2c and R2d each independently represent a hydrogen atom or a halogen atom, R3a, R3b and R3c each independently represent a hydrogen atom or a halogen atom, and Rad represents a hydrogen atom.]
Among them, a compound represented by the following formula (A) that can be produced by the following method is reported in Patent Literature 8.
[In the formulae, Ac represents an acetyl group.]
(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropylmethanol (A-5) produced in the above production method can be produced by reacting {(1R, 2S)-2-(3-fluorophenyl)-2-[(tosyloxy)methyl]cyclopropyl}methyl acetate produced from a compound (A-3) with 2,4-dimethylpyrimidine-5-ol (step (g)) and subsequent hydrolysis (step (d)) as shown in the following steps.
[In the formulae, Ac represents an acetyl group and Ts represents a p-toluenesulfonyl group.]